Prorenin is the least understood component of the renin-angiotensin system. Although it is the precursor of renin only 10% of renal prorenin is processed to renin. The remainder is secreted constitutively, as it is synthesized, resulting in ten times more prorenin than renin in the general circulation. Moreover, prorenin processing to renin does not occur in those extrarenal, primarily reproductive organs that express the renin gene. The reason for this profusion and wide distribution of prorenin is unknown. Clinically, elevated plasma prorenin is a risk factor for renal and retinal vascular disease in diabetic patients. Our laboratory is one of a few that continue to study prorenin. We previously showed that prorenin is not converted to renin in the circulation and that blood pressure does not rise when human prorenin is infused into monkeys (it actually falls). We also observed that high prorenin levels are associated with increased renal blood flow. These and other studies led us to propose that prorenin has vasodilator properties, localized to specific target organs and that the high prorenin of the diabetic patient predisposes to hyperperfusion injury. Investigation of this hypothesis led to our discovery of specific prorenin binding sites on membranes from kidney, liver, testis and other organs and competition between renin and prorenin for this binding site. This led to our hypothesis that prorenin, although biochemically inactive, is associated with vasodilator properties because it competes with renin for binding sites in target organs thereby reducing the vasoconstrictor activity of bound renin and increasing tissue blood flow. Specifically we propose to infuse pure, homologous prorenin to rats to investigate its physiological effects and to determine whether these properties are intrinsic to the prorenin molecule or occur by virtue of competition with renin for binding sites. Studies will be performed using unique reagents prepared in our laboratory: pure recombinant rat renin and prorenin, synthetic rat prosequence antibodies and anti-renin antibodies. Dr. Lufei Hu, a young, but well trained physiologist will infuse prorenin, acutely into anesthetized rats and chronically into awake rats with low endogenous plasma prorenin levels infused with various levels of renin or Ang II. Hypertensive rat models will also be infused. Effects on BP, renal function and components of the renin-angiotensin-aldosterone system and testosterone will be measured. The results of these studies will define plasma renin/prorenin interactions at particular tissue sites involved in cardiovascular homeostasis. The proposed studies may also improve understanding of the pathophysiology of hypertensive and diabetic vascular diseases, provide new candidate genes for genetic analysis and lead to more specific therapeutic strategies.